SEA 2024 Standards for Global Control of Vascular Risk. / Estándares de la Sociedad Española de Arteriosclerosis 2024 para el control global del riesgo vascular.

One of the objectives of the Spanish Society of Arteriosclerosis is to contribute to the knowledge, prevention and treatment of vascular diseases, which are the leading cause of death in Spain and entail a high degree of disability and health expenditure. Atherosclerosis is a multifactorial disease and its prevention requires a global approach that takes into account the associated risk factors. This document summarises the current evidence and includes recommendations for patients with established vascular disease or at high vascular risk: it reviews the symptoms and signs to evaluate, the laboratory and imaging procedures to request routinely or in special situations, and includes the estimation of vascular risk, diagnostic criteria for entities that are vascular risk factors, and general and specific recommendations for their treatment. Finally, it presents aspects that are not usually referenced in the literature, such as the organisation of a vascular risk consultation.

Apelin-13: A Protective Role in Vascular Diseases.

Vascular disease is a common problem with high mortality all over the world. Apelin-13, a key subtype of apelin, takes part in many physiological and pathological responses via regulating many target genes and target molecules or participating in many signaling pathways. More and more studies have demonstrated that apelin-13 is implicated in the onset and progression of vascular disease in recent years. It has been shown that apelin-13 could ameliorate vascular disease by inhibiting inflammation, restraining apoptosis, suppressing oxidative stress, and facilitating autophagy. In this article, we sum up the progress of apelin-13 in the occurrence and development of vascular disease and offer some insightful views about the treatment and prevention strategies of vascular disease.

Role of ascorbic acid in cardiac allograft vasculopathy.

PURPOSE OF THE REVIEW: Cardiac allograft vasculopathy (CAV) is a progressive fibroproliferative disease which occurs after heart transplantation and is associated with significant long-term morbidity and mortality. Currently available strategies including statins, mammalian target of rapamycin (mTOR) inhibitors, and revascularization, have limited overall effectiveness in treating this pathology once the disease process is established. mTOR inhibitors, while effective when used early in the disease process, are not well tolerated, and hence not routinely used in post-transplant care. RECENT DATA: Recent work on rodent models have given us a novel mechanistic understanding of effects of ascorbic acid in preventing CAV. TET methyl cytosine dioxygenase2 (TET2) reduces vascular smooth muscle cell (VSMC) apoptosis and intimal thickening. TET2 is repressed by interferon γ (IFNγ) in the setting of CAV. Ascorbic acid has been shown to promote TET2 activity and attenuate allograft vasculopathy in animal models and CAV progression in a small clinical trial. SUMMARY: CAV remains a challenging disease process and needs better preventative strategies. Ascorbic acid improves endothelial dysfunction, reduces reactive oxygen species, and prevents development of intimal hyperplasia by preventing smooth muscle cell apoptosis and hyperproliferation. Further large-scale randomized control studies of ascorbic acid are needed to establish the role in routine post-transplant management.

The Spanish Scientific Societies before the ESC 2021 guidelines on vascular disease prevention: Generalizing the measurement of albuminuria to identify vascular risk and prevent vascular disease.

The 2021 guidelines on the prevention of vascular disease (VD) in clinical practice published by the European Society of Cardiology (ESC) and supported by 13 other European scientific societies recognize the key role of screening for chronic kidney disease (CKD) in the prevention of VD. Vascular risk in CKD is categorized based on measurements of estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR). Thus, moderate CKD is associated with a high vascular risk and severe CKD with a very high vascular risk requiring therapeutic action, and there is no need to apply other vascular risk scores when vascular risk is already very high due to CKD. Moreover, the ESC indicates that vascular risk assessment and the subsequent decision algorithm should start with measurement of eGFR and ACR. To optimize the implementation of the ESC 2021 guidelines on the prevention of CVD in Spain, we consider that: 1) Urine testing for albuminuria using ACR should be part of the clinical routine at the same level as blood glucose, cholesterolemia, and GFR estimation when these are used to make decisions on CVD risk. 2) Spanish public and private health services should have the necessary means and resources to optimally implement the ESC 2021 guidelines for the prevention of CVD in Spain, including ACR testing.

Impact of vascular screening interventions on perceived threat, efficacy beliefs and behavioural intentions: a systematic narrative review.

Health-related behaviours contribute to the global burden of cardiovascular disease (CVD). Cardiovascular imaging can be used to screen asymptomatic individuals for increased risk of CVD to enable earlier interventions to promote health-related behaviours to prevent or reduce CVD risk. Some theories of behaviour and behaviour change assume that engagement in a given behaviour is a function of individual threat appraisals, beliefs regarding the performance of behaviour, self-efficacy for performing the desired behaviour and/or dispositions to act (e.g. behavioural intentions). To date, little is known about the impact of cardiovascular imaging interventions on these constructs. This article summarises evidence related to perceived threat, efficacy beliefs, and behavioural intentions after CVD screening. We identified 10 studies (2 RCTs and 8 non-randomised studies, n = 2498) through a combination of screening citations from published systematic reviews and meta-analyses and searching electronic databases. Of these, 7 measured behavioural intentions and perceived susceptibility and 3 measured efficacy beliefs. Findings showed largely encouraging effects of screening interventions on bolstering self-efficacy beliefs and strengthening behavioural intentions. Imaging results that suggest the presence of coronary or carotid artery disease also increased perceived susceptibility to CVD. However, the review also identified some gaps in the literature, such as a lack of guiding theoretical frameworks and assessments of critical determinants of health-related behaviours. By carefully considering the key issues highlighted in this review, we can make significant strides towards reducing CVD risks and improving population health.

This systematic narrative review sought to comprehensively report evidence related to individual responses to cardiovascular screening interventions. Theoretically, the study builds upon theories based on the cognitive perspective (e.g. Health Belief Model, Protection Motivation Theory), which supports the examination of individual perceptions of negative health-related outcomes or health risk, beliefs regarding the performance of a behaviour or outcome expectancies (e.g. perceived benefits of behavioural performance), personal control or capacity to perform a behaviour and/or willingness to invest the effort to engage in behaviour after behavioural intervention delivery. These concepts are considered key predictors of health-related behaviours and have been examined in several public health interventions. Using a variety of search strategies, studies that reported outcomes of interest were identified. Some studies showed that cardiovascular screening interventions may help people form the desired intention to engage in health-related behaviours. We also observed (largely) encouraging effects of cardiovascular screening interventions on individual confidence to engage in health-related behaviours and understanding of personal health risks. However, we identified some limitations in the design, delivery and outcomes assessed in the studies included. For future research, key recommendations to inform the design and delivery of health behaviour interventions are provided.

[Call attention to the role of Beijing Vascular Health Stratification in clinical practice of intellectualized and digital heart and vascular health management medical model in China].

Early comprehensive assessment and early intervention of vascular disease, and the life-time maintenance of vascular health are the key to effectively preventing death and disability in end-stage of heart, brain, kidney and peripheral vascular events. Based on this concept, it is necessary to establish a professional clinical discipline of "vascular medicine" which is based on the systemic vascular bed, with measures on prevention, treatment, rehabilitation and intellectualized and digital vascular health management throughout the life cycle for different vascular lesions and different degree of vascular injury. The aim of the establishment of Beijing Vascular Health Stratification (BVHS) is to give a comprehensive and dynamic assessment of vascular health based on the concept of vascular medicine, to conduct individualized analysis of the results, to classify the degree of injury on vascular structure and function, to carry out individualized intervention, and eventually achieve targeted precise prevention and management, establish newly intellectualized and digital vascular health management medical model in China, for effectively reducing the incidence of cardiovascular events.

Dietary iron restriction protects against vaso-occlusion and organ damage in murine sickle cell disease.

Sickle cell disease (SCD) is an inherited disorder resulting from a ß-globin gene mutation, and SCD patients experience erythrocyte sickling, vaso-occlusive episodes (VOE), and progressive organ damage. Chronic hemolysis, inflammation, and repeated red blood cell transfusions in SCD can disrupt iron homeostasis. Patients who receive multiple blood transfusions develop iron overload, and another subpopulation of SCD patients manifest iron deficiency. To elucidate connections between dietary iron, the microbiome, and SCD pathogenesis, we treated SCD mice with an iron-restricted diet (IRD). IRD treatment reduced iron availability and hemolysis, decreased acute VOE, and ameliorated chronic organ damage in SCD mice. Our results extend previous studies indicating that the gut microbiota regulate disease in SCD mice. IRD alters microbiota load and improves gut integrity, together preventing crosstalk between the gut microbiome and inflammatory factors such as aged neutrophils, dampening VOE, and organ damage. These findings provide strong evidence for the therapeutic potential of manipulating iron homeostasis and the gut microbiome to ameliorate SCD pathophysiology. Many treatments, which are under development, focus on lowering the systemic iron concentration to relieve disease complications, and our data suggest that iron-induced changes in microbiota load and gut integrity are related- and novel-therapeutic targets.

Mechanistic insights into dietary (poly)phenols and vascular dysfunction-related diseases using multi-omics and integrative approaches: Machine learning as a next challenge in nutrition research.

Dietary (poly)phenols have been extensively studied for their vasculoprotective effects and consequently their role in preventing or delaying onsets of cardiovascular and metabolic diseases. Even though early studies have ascribed the vasculoprotective properties of (poly)phenols primarily on their putative free radical scavenging properties, recent data indicate that in biological systems, (poly)phenols act primarily through genomic and epigenomic mechanisms. The molecular mechanisms underlying their health properties are still not well identified, mainly due to the use of physiologically non-relevant conditions (native molecules or extracts at high concentrations, rather than circulating metabolites), but also due to the use of targeted genomic approaches aiming to evaluate the effect only on few specific genes, thus preventing to decipher detailed molecular mechanisms involved. The use of state-of-the-art untargeted analytical methods represents a significant breakthrough in nutrigenomics, as these methods enable detailed insights into the effects at each specific omics level. Moreover, the implementation of multi-omics approaches allows integration of different levels of regulation of cellular functions, to obtain a comprehensive picture of the molecular mechanisms of action of (poly)phenols. In combination with bioinformatics and the methods of machine learning, multi-omics has potential to make a huge contribution to the nutrition science. The aim of this review is to provide an overview of the use of the omics, multi-omics, and integrative approaches in studying the vasculoprotective properties of dietary (poly)phenols and address the potentials for use of the machine learning in nutrigenomics.

Suppression of trimethylamine N-oxide with DMB mitigates vascular dysfunction, exercise intolerance, and frailty associated with a Western-style diet in mice.

Consumption of a Western-style diet (WD; high fat, high sugar, low fiber) is associated with impaired vascular function and increased risk of cardiovascular diseases (CVD), which could be mediated partly by increased circulating concentrations of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO). We investigated if suppression of TMAO with 3,3-dimethyl-1-butanol (DMB; inhibitor of microbial TMA lyase) in mice could prevent: 1) WD-induced vascular endothelial dysfunction and aortic stiffening and 2) WD-induced reductions in endurance exercise tolerance and increases in frailty, as both are linked to WD, vascular dysfunction, and increased CVD risk. C57BL/6N mice were fed standard chow or WD (41% fat, ∼25% sugar, 4% fiber) for 5 mo beginning at ∼2 mo of age. Within each diet, mice randomly received (n = 11-13/group) normal drinking water (control) or 1% DMB in drinking water for the last 8 wk (from 5 to 7 mo of age). Plasma TMAO was increased in WD-fed mice but suppressed by DMB. WD induced endothelial dysfunction, assessed as carotid artery endothelium-dependent dilation to acetylcholine, and progressive increases in aortic stiffness (measured serially in vivo as pulse wave velocity), both of which were fully prevented by supplementation with DMB. Endurance exercise tolerance, assessed as time to fatigue on a rotarod test, was impaired in WD-fed mice but partially recovered by DMB. Lastly, WD-induced increases in frailty (31-point index) were prevented by DMB. Our findings indicate DMB or other TMAO-lowering therapies may be promising for mitigating the adverse effects of WD on physiological function, and thereby reducing risk of chronic diseases.NEW & NOTEWORTHY We provide novel evidence that increased circulating concentrations of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) contribute to vascular dysfunction associated with consumption of a Western-style diet and that this dysfunction can be prevented by suppressing TMAO with DMB, thereby supporting translation of this compound to humans. Furthermore, to our knowledge, we present the first evidence of the role of TMAO in mediating impairments in endurance exercise tolerance and increased frailty in any context.

Spirulina extract improves age-induced vascular dysfunction.

CONTEXT: Vascular dysfunction is considered a hallmark of ageing that has been associated with altered vasomotor responses, in which nitric oxide (NO) and reactive oxygen species participate. The consumption of Spirulina extracts, with antioxidant properties, increased recently. OBJECTIVE: This study investigates the effect of Spirulina aqueous extract (SAE) on the vascular function of the aorta from aged rats. MATERIALS AND METHODS: Aortic segments from aged male Sprague-Dawley rats (20-22 months old) were exposed to SAE (0.1% w/v, for 3 h) to analyse: (i) the vasodilator response induced by acetylcholine (ACh), by the NO donor sodium nitroprusside (SNP), by the carbon monoxide releasing molecule (CORM) and by the KATP channel opener, cromakalim (CK); (ii) the vasoconstrictor response induced by KCl and noradrenaline (NA); (iii) the production of NO and superoxide anion, and (iv) the expression of the p-eNOS and HO-1 proteins. RESULTS: Incubation with SAE increased the expression of p-eNOS (1.6-fold) and HO-1 (2.0-fold), enhanced NO release (1.4-fold in basal and 1.9-fold in ACh-stimulated conditions) while decreased the production of superoxide (0.7-fold). SAE also increased the sensitivity (measured as pEC50) to ACh (control: -7.06 ± 0.11; SAE: -8.16 ± 0.21), SNP (control: -7.96 ± 0.16; SAE: -9.11 ± 0.14) and CK (control: -7.05 ± 0.39; SAE: -8.29 ± 0.53), and potentiated the response to KCl (1.3-fold) and to NA (1.7-fold). CONCLUSION: The antioxidant properties of SAE improved the vasomotor responses of aorta from aged rats. These results may support the use of Spirulina as a protection against vascular dysfunction.

The Effect of Diet on Cardiovascular Disease, Heart Disease, and Blood Vessels.

The Effect of Diet on Cardiovascular Disease, Heart Disease, and Blood Vessels [...].

Endothelial SIRT1 as a Target for the Prevention of Arterial Aging: Promises and Challenges.

ABSTRACT: SIRT1, a member of the sirtuin family of longevity regulators, possesses potent activities preventing vascular aging. The expression and function of SIRT1 in endothelial cells are downregulated with age, in turn causing early vascular aging and predisposing various vascular abnormalities. Overexpression of SIRT1 in the vascular endothelium prevents aging-associated endothelial dysfunction and senescence, thus the development of hypertension and atherosclerosis. Numerous efforts have been directed to increase SIRT1 signaling as a potential strategy for different aging-associated diseases. However, the complex mechanisms underlying the regulation of SIRT1 have posed a significant challenge toward the design of specific and effective therapeutics. This review aimed to provide a summary on the regulation and function of SIRT1 in the vascular endothelium and to discuss the different approaches targeting this molecule for the prevention and treatment of age-related cardiovascular and cerebrovascular diseases.

Ginsenoside Rb1 attenuates age-associated vascular impairment by modulating the Gas6 pathway.

CONTEXT: Ginsenoside Rb1 (Rb1) exerts many beneficial effects and protects against cardiovascular disease. OBJECTIVE: To investigate whether Rb1 could attenuate age-related vascular impairment and identify the mechanism. MATERIALS AND METHODS: Female C57BL/6J mice aged 2 and 18 months, randomly assigned to Young, Young + 20 mg/kg Rb1, Old + vehicle, Old + 10 mg/kg Rb1 and Old + 20 mg/kg Rb1 groups, were daily intraperitoneal injected with vehicle or Rb1 for 3 months. The thoracic aorta segments were used to inspect the endothelium-dependent vasorelaxation. Left thoracic aorta tissues were collected for histological or molecular expression analyses, including ageing-related proteins, markers relevant to calcification and fibrosis, and expression of Gas6/Axl. RESULTS: We found that in Old + vehicle group, the expression of senescence proteins and cellular adhesion molecules were significantly increased, with worse endothelium-dependent thoracic aorta relaxation (58.35% ± 2.50%) than in Young group (88.84% ± 1.20%). However, Rb1 treatment significantly decreased the expression levels of these proteins and preserved endothelium-dependent relaxation in aged mice. Moreover, Rb1 treatment also reduced calcium deposition, collagen deposition, and the protein expression levels of collagen I and collagen III in aged mice. Furthermore, we found that the downregulation of Gas6 protein expression by 41.72% and mRNA expression by 52.73% in aged mice compared with young mice was abrogated by Rb1 treatment. But there was no significant difference on Axl expression among the groups. CONCLUSIONS: Our study confirms that Rb1 could ameliorate vascular injury, suggesting that Rb1 might be a potential anti-ageing related vascular impairment agent.

The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats.

Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9-10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8-10 rats) or 50µM CANA (IR + CANA, n = 9-11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.

Pregnancy-Related Aortic Complications in Women With Marfan Syndrome.

BACKGROUND: The risk of pregnancy-associated vascular complications in Marfan syndrome (MFS) is uncertain because of ascertainment bias, prepartum lack of knowledge of diagnosis, and insufficient peripartum imaging data. Furthermore, U.S. and European guidelines differ in pregnancy recommendations in MFS. OBJECTIVES: This study describes a single-center experience of 169 MFS women to address these gaps. METHODS: Clinical, imaging, and pregnancy history were compared in never vs ever-pregnant MFS women, and pregnancy-associated vascular complications were described. RESULTS: A total of 74 ever-pregnant women had 112 live births. Elective aortic root replacement occurred at a younger age in never-pregnant women (33 years vs 42 years; P = 0.0026). Although aortic dissection prevalence did not differ between never-pregnant vs ever-pregnant women (23% vs 31%; P = 0.25), it tended to occur at an earlier age in the former group (38 years vs 45 years; P = 0.07). Of observed "sanctioned" pregnancies with prepartum diameters ≤4.5 cm, mean pregnancy-related aortic diameters remained stable. In total, 5 dissections were associated with pregnancy: 2 type A in women unaware of their diagnosis; and 2 type B and 1 isolated coronary artery dissection in women aware of their diagnosis. Dissection rates were 5-fold higher in the pregnancy vs nonpregnancy period. CONCLUSIONS: Pregnancy-related type A dissection only occurred in patients unaware of their diagnosis. Type B dissection remains an unpredictable complication. Although there were baseline differences between the never- and ever-pregnant groups, no difference in dissection risk was observed outside the peripartum period. Those with prepartum aortic diameters between 4.0 and 4.5 cm demonstrated stable aortic dimensions throughout pregnancy. These findings provide a rationale to update existing U.S. guidelines for the management of pregnancy in MFS.

Decision Science Can Inform Clinical Trade-Offs Regarding Cardiotoxic Cancer Treatments.

Cancer treatment-related cardiotoxicity (ie, heart failure, coronary artery disease, vascular diseases, arrhythmia) is a growing cancer survivorship concern within oncology practice; heart disease is the leading cause of noncancer death in cancer survivors and surpasses cancer as the leading cause of death for some cancers with higher survival rates. The issue of cardiotoxicity introduces a critical tradeoff that must be acknowledged and reconciled in clinical oncology practice: treating cancer aggressively and effectively in the present vs preventing future cardiotoxicity. Although many cancers must be treated as aggressively as possible, for others, multiple treatment options are available. Yet even when effective and less cardiotoxic treatments are available, they are not always chosen. Wariness to choose equally effective but less cardiotoxic treatment options may result in part from providers' and patients' reliance on "cognitive heuristics," or mental shortcuts that people (including, research shows, medical professionals) use to simplify complex judgments. These heuristics include delay discounting, availability and affect heuristics, and default bias. In the current commentary, we describe relevant research that illuminates how use of heuristics leads to biased medical decision making and translate how this research may apply when the tradeoff between aggressive cancer treatment and preventing future cardiotoxicity is considered. We discuss the implications of these biases in oncology practice, offer potential solutions to reduce bias, and call for future research in this area.

Riesgo de tromboembolismo venoso y uso adecuado de terapia tromboprofiláctica / Risk of venous thromboembolism and adequate use of thromboprophylactic therapy

INTRODUCCIÓN. El tromboembolismo venoso es una complicación prevenible en pacientes hospitalizados y la estratificación del riesgo mejora la seguridad del paciente, su valoración evita su ocurrencia. OBJETIVO. Evaluar el riesgo de tromboembolismo venoso y uso adecuado de terapia tromboprofiláctica en pacientes hospitalizados. MATERIALES Y MÉTODOS. Estudio analítico transversal. Población de 412 y muestra de 373 pacientes encuestados, distribuidos: 186 en Unidades Clínicas, 163 en Unidades Quirúrgicas y 24 en Obstetricia del Hospital de Especialidades Carlos Andrade Marín, desde el 21 al 23 de febrero del 2019. La tabulación y análisis de datos se realizó en el programa estadístico International Business Machines Statistical Package for the Social Sciences, versión 21. RESULTADOS. Se categorizó como alto riesgo de tromboembolismo venoso al 76,67% (286; 373) de pacientes; 49,46% (144; 163) postquirúrgicos y 69,40% (129; 286) clínicos de alto riesgo de tromboembolismo venoso, recibiendo tromboprofilaxis farmacológica de forma adecuada el 38,80% (56; 144) de quirúrgicos y 57,40% (74; 129) de clínicos. CONCLUSIÓN. Se determinó que el uso de tromboprofilaxis no farmacológica y farmacológica con heparina de bajo peso molecular en pacientes hospitalizados con riesgo de tromboembolismo venoso, fue bajo.

INTRODUCTION. Venous thromboembolism is a preventable complication in hospitalized patients and risk stratification improves patient safety, its ocurrence is prevented by its assessment. OBJECTIVE. To evaluate the risk of venous thromboembolism and ade-quate use of thromboprophylactic therapy in hospitalized patients. MATERIALS AND METHODS. Cross-sectional analytical study. Population of 412 and sample of 373 patients surveyed, distributed: 186 in clinical wards, 163 in surgical wards and 24 in obstetrics of the Carlos Andrade Marín Specialties Hospital, from february 21 to 23, 2019. Data tabulation and analysis was performed in the statistical program International Business Machines Statistical Package for the Social Sciences, version 21. RESULTS. 76,67% (286; 373) of patients were categorized as high risk of venous thromboembolism; 49,46% (144; 163) post-surgical and 69,40% (129; 286) clinical patients as high risk of venous thromboembo-lism, with 38,80% (56; 144) of surgical and 57,40% (74; 129) of clinical patients receiving adequate pharmacological thromboprophylaxis. CONCLUSIONS. The use of nonpharma-cological and pharmacological thromboprophylaxis with low-molecular-weight heparin in hospitalized patients at risk of venous thromboembolism was low.

C21 preserves endothelial function in the thoracic aorta from DIO mice: role for AT2, Mas and B2 receptors.

Compound 21 (C21), a selective agonist of angiotensin II type 2 receptor (AT2R), induces vasodilation through NO release. Since AT2R seems to be overexpressed in obesity, we hypothesize that C21 prevents the development of obesity-related vascular alterations. The main goal of the present study was to assess the effect of C21 on thoracic aorta endothelial function in a model of diet-induced obesity (DIO) and to elucidate the potential cross-talk among AT2R, Mas receptor (MasR) and/or bradykinin type 2 receptor (B2R) in this response. Five-week-old male C57BL6J mice were fed a standard (CHOW) or a high-fat diet (HF) for 6 weeks and treated daily with C21 (1 mg/kg p.o) or vehicle, generating four groups: CHOW-C, CHOW-C21, HF-C, HF-C21. Vascular reactivity experiments were performed in thoracic aorta rings. Human endothelial cells (HECs; EA.hy926) were used to elucidate the signaling pathways, both at receptor and intracellular levels. Arteries from HF mice exhibited increased contractions to Ang II than CHOW mice, effect that was prevented by C21. PD123177, A779 and HOE-140 (AT2R, Mas and B2R antagonists) significantly enhanced Ang II-induced contractions in CHOW but not in HF-C rings, suggesting a lack of functionality of those receptors in obesity. C21 prevented those alterations and favored the formation of AT2R/MasR and MasR/B2R heterodimers. HF mice also exhibited impaired relaxations to acetylcholine (ACh) due to a reduced NO availability. C21 preserved NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways. In conclusion, C21 favors the interaction among AT2R, MasR and B2R and prevents the development of obesity-induced endothelial dysfunction by stimulating NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways.